| Structural highlights
5b83 is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | UBC (HUMAN), OPTN, FIP2, GLC1E, HIP7, HYPL, NRP (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[OPTN_HUMAN] Amyotrophic lateral sclerosis;Congenital glaucoma. Primary open angle glaucoma 1E (GLC1E) [MIM:137760]: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. The disease is asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] [5] [6] Normal pressure glaucoma (NPG) [MIM:606657]: A primary glaucoma characterized by intraocular pression consistently within the statistically normal population range. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.[7] Amyotrophic lateral sclerosis 12 (ALS12) [MIM:613435]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Note=The disease is caused by mutations affecting the gene represented in this entry.[8]
Function
[UBC_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[9] [10] [OPTN_HUMAN] Plays an important role in the maintenance of the Golgi complex, in membrane trafficking, in exocytosis, through its interaction with myosin VI and Rab8. Links myosin VI to the Golgi complex and plays an important role in Golgi ribbon formation. Negatively regulates the induction of IFNB in response to RNA virus infection. Plays a neuroprotective role in the eye and optic nerve. Probably part of the TNF-alpha signaling pathway that can shift the equilibrium toward induction of cell death. May act by regulating membrane trafficking and cellular morphogenesis via a complex that contains Rab8 and hungtingtin (HD). May constitute a cellular target for adenovirus E3 14.7, an inhibitor of TNF-alpha functions, thereby affecting cell death.[11] [12] [13]
Publication Abstract from PubMed
Optineurin (OPTN) mutations cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and glaucoma. Although the ALS-associated E478G mutation in the UBAN domain of OPTN reportedly abolishes its NF-kappaB suppressive activity, the precise molecular basis in ALS pathogenesis still remains unclear. Here we report that the OPTN-UBAN domain is crucial for NF-kappaB suppression. Our crystal structure analysis reveals that OPTN-UBAN binds linear ubiquitin with homology to NEMO. TNF-alpha-mediated NF-kappaB activation is enhanced in OPTN-knockout cells, through increased ubiquitination and association of TNF receptor (TNFR) complex I components. Furthermore, OPTN binds caspase 8, and OPTN deficiency accelerates TNF-alpha-induced apoptosis by enhancing complex II formation. Immunohistochemical analyses of motor neurons from OPTN-associated ALS patients reveal that linear ubiquitin and activated NF-kappaB are partially co-localized with cytoplasmic inclusions, and that activation of caspases is elevated. Taken together, OPTN regulates both NF-kappaB activation and apoptosis via linear ubiquitin binding, and the loss of this ability may lead to ALS.
Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis.,Nakazawa S, Oikawa D, Ishii R, Ayaki T, Takahashi H, Takeda H, Ishitani R, Kamei K, Takeyoshi I, Kawakami H, Iwai K, Hatada I, Sawasaki T, Ito H, Nureki O, Tokunaga F Nat Commun. 2016 Aug 24;7:12547. doi: 10.1038/ncomms12547. PMID:27552911[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Heon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002 Feb 8;295(5557):1077-9. PMID:11834836 doi:10.1126/science.1066901
- ↑ Leung YF, Fan BJ, Lam DS, Lee WS, Tam PO, Chua JK, Tham CC, Lai JS, Fan DS, Pang CP. Different optineurin mutation pattern in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2003 Sep;44(9):3880-4. PMID:12939304
- ↑ Alward WL, Kwon YH, Kawase K, Craig JE, Hayreh SS, Johnson AT, Khanna CL, Yamamoto T, Mackey DA, Roos BR, Affatigato LM, Sheffield VC, Stone EM. Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma. Am J Ophthalmol. 2003 Nov;136(5):904-10. PMID:14597044
- ↑ Willoughby CE, Chan LL, Herd S, Billingsley G, Noordeh N, Levin AV, Buys Y, Trope G, Sarfarazi M, Heon E. Defining the pathogenicity of optineurin in juvenile open-angle glaucoma. Invest Ophthalmol Vis Sci. 2004 Sep;45(9):3122-30. PMID:15326130 doi:10.1167/iovs.04-0107
- ↑ Funayama T, Ishikawa K, Ohtake Y, Tanino T, Kurosaka D, Kimura I, Suzuki K, Ideta H, Nakamoto K, Yasuda N, Fujimaki T, Murakami A, Asaoka R, Hotta Y, Tanihara H, Kanamoto T, Mishima H, Fukuchi T, Abe H, Iwata T, Shimada N, Kudoh J, Shimizu N, Mashima Y. Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma. Invest Ophthalmol Vis Sci. 2004 Dec;45(12):4359-67. PMID:15557444 doi:45/12/4359
- ↑ Fuse N, Takahashi K, Akiyama H, Nakazawa T, Seimiya M, Kuwahara S, Tamai M. Molecular genetic analysis of optineurin gene for primary open-angle and normal tension glaucoma in the Japanese population. J Glaucoma. 2004 Aug;13(4):299-303. PMID:15226658
- ↑ Umeda T, Matsuo T, Nagayama M, Tamura N, Tanabe Y, Ohtsuki H. Clinical relevance of optineurin sequence alterations in Japanese glaucoma patients. Ophthalmic Genet. 2004 Jun;25(2):91-9. PMID:15370540 doi:10.1080/13816810490514298
- ↑ Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010 May 13;465(7295):223-6. doi: 10.1038/nature08971. Epub 2010 Apr 28. PMID:20428114 doi:10.1038/nature08971
- ↑ Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006 Mar 17;21(6):737-48. PMID:16543144 doi:S1097-2765(06)00120-1
- ↑ Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53. doi: 10.1042/BST0370937. PMID:19754430 doi:10.1042/BST0370937
- ↑ Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Heon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002 Feb 8;295(5557):1077-9. PMID:11834836 doi:10.1126/science.1066901
- ↑ Sahlender DA, Roberts RC, Arden SD, Spudich G, Taylor MJ, Luzio JP, Kendrick-Jones J, Buss F. Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis. J Cell Biol. 2005 Apr 25;169(2):285-95. Epub 2005 Apr 18. PMID:15837803 doi:10.1083/jcb.200501162
- ↑ Mankouri J, Fragkoudis R, Richards KH, Wetherill LF, Harris M, Kohl A, Elliott RM, Macdonald A. Optineurin negatively regulates the induction of IFNbeta in response to RNA virus infection. PLoS Pathog. 2010 Feb 19;6(2):e1000778. doi: 10.1371/journal.ppat.1000778. PMID:20174559 doi:10.1371/journal.ppat.1000778
- ↑ Nakazawa S, Oikawa D, Ishii R, Ayaki T, Takahashi H, Takeda H, Ishitani R, Kamei K, Takeyoshi I, Kawakami H, Iwai K, Hatada I, Sawasaki T, Ito H, Nureki O, Tokunaga F. Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis. Nat Commun. 2016 Aug 24;7:12547. doi: 10.1038/ncomms12547. PMID:27552911 doi:http://dx.doi.org/10.1038/ncomms12547
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